Diltiazem is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and thus exerts potent cardio-vascular effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia and hypertension, while displaying a low incidence of side effects. The first dosage forms of diltiazem sold in the United States were tablets containing 30 mg or 60 mg of diltiazem hydrochloride sold under this tradename Cardizem by Marion Laboratories Inc. Single oral doses of 30 mg to 120 mg of Cardizem tablets result in peak plasma level about 2 to 3 hours after ingestion, and the elimination half-life is about 3 to 5 hours. Because of the relatively rapid absorption of diltiazem from such tablets and rapid elimination, the usual dosage regimen for such tablets is for the daily dosage to be taken in divided doses, three or four times daily. The need for such frequent administration may reduce patient compliance and produce irregular blood levels. Thus adverse therapeutic effects can arise. It thus became apparent that it would be preferable to administer diltiazem hydrochloride in a dosage form that releases the diltiazem hydrochloride much more slowly than Cardizem tablets, so as to enable the frequency of ingestion by the patient to be reduced from three or four times daily to once daily.
A dosage form of diltiazem hydrochloride that controls the rate of release to enable once daily administration is now sold in the United States under the trademark Cardizem CD, also by Marion Laboratories Inc. Cardizem CD is sold as capsules containing a multitude of pellets. The pellets are made using core seeds to which is applied a first coating containing the diltiazem hydrochloride. Over the first coating, further coatings of polymers are applied which serve to slow down and control the rate at which the diltiazem hydrochloride is released from the pellets in gastrointestinal fluids. The composition of the pellets contained in Cardizem CD capsules is described,in more detail in U.S. Pat. No. 4,894,240. While the formulation of Cardizem CD capsules successfully accomplishes gradual release to enable once daily administration, the procedures required to make and coat the pellets are time consuming and expensive.
Another formulation Of diltiazem hydrochloride suitable for once daily administration is sold in the United States under the tradename Dilacor XR by Rhone-Poulenc Rorer Pharmaceuticals Inc.
Dilacor XR is produced as two-piece hard gelatin capsules, with each capsule containing a multitude of tablets. The 180 mg strength of Dilacor XR contains three tablets and the 240 mg strength contains four tablets. The same tablets are used in both capsules, and each tablet contains 60 mg of diltiazem hydrochloride.
The tablets used in Dilacor XR are made in accordance with the invention of U.S. Pat. No. 4,839,177.
Each tablet weights about 205 mg and comprises of a cylindrical core containing diltiazem hydrochloride mixed with inactive ingredients which include a polymer that swells and forms a gel upon contact with aqueous fluids. Because the gel has high viscosity it swells and dissolves only very slowly in the gastrointestinal fluids to thereby retard the rate of release of the diltiazem hydrochloride. To further retard the release, insoluble polymeric platforms are affixed to the top and bottom of the cylindrical core, thus leaving only the periphery exposed to the gastrointestinal fluid. The formula of Dilacor XR capsules successfully accomplishes gradual release to enable once daily dosing, but, just as is the case with the Cardizem CD formulation, the Dilacor XR formulation requires complex and expensive procedures to produce. In particular, production of the tablets contained in Dilacor XR capsules requires production of cores containing the diltiazem hydrochloride and the affixing thereto of the insoluble platforms. Another difficulty with the Dilacor XR formulation is that the tablets are larger than desirable, so that the capsules containing 4 tablets must be size 00, which have an external diameter of about 8.5 mm and length of about 23.7 mm. These are difficult to, swallow because of this large size.
In view of the aforesaid problems with prior art formulations, it is an object of the invention to produce a dosage form of diltiazem hydrochloride with controlled release suitable for once daily administration, in the form of easy-to-make compressed tablets, and to make such tablets small enough such that four tablets, each containing 60 mg of diltiazem hydrochloride, can be contained within a gelatin capsule of size 0, which is a smaller size than size 00.